Effects of R56865, an Na+- and Ca2+-Overload Inhibitor, on Myocardial Injury in Ischemic, Reperfused Porcine Hearts

The cardioprotective effect of R56865, an Na(+)- and Ca(2+)-overload inhibitor, was studied in 20 regionally ischemic reperfused (I/R) porcine hearts. Ten pigs were treated with a single intravenous (i.v.) injection of 0.4 mg/kg 15 min before occlusion of the distal left anterior descending coronary artery (LAD) for 45 min. Ten other animals served as controls. Infarct size (IS) was determined as percentage of infarcted (tetrazolium method) to ischemic (dye technique) myocardium after 24-h reperfusion. Regional systolic shortening (SS) was determined by sonomicrometry. Fifteen minutes after i.v. administration of R56865, a significant decrease in heart rate (HR) (from 83 +/- 15 to 74 +/- 16 beats/min), dP/dtmax (from 2,033 +/- 604 to 1,822 +/- 524 mm Hg/s), LAD blood flow (BF, from 17 +/- 7 to 14 +/- 7 ml/min), and calculated global myocardial O2 consumption (MVO2) (from 5.9 +/- 0.9 to 5.4 +/- 0.9 ml O2/min x 100 g) was observed. Although this investigational drug attenuated the increase in HR during early reperfusion, the incidence of ventricular fibrillation (VF) was not affected during either ischemia or reperfusion. R56865 reduced IS by 24% from 67.1 +/- 16% (control group) to 50.8 +/- 13%. In addition, this treatment improved systolic shortening after 24-h reperfusion from 6 +/- 8% (control group) to 15 +/- 9%. Our results support the concept that inhibition of intracellular Na(+)- and Ca(2+)-overload is a promising new principle in treatment of myocardial I/R.